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三维肿瘤球模型应用于肿瘤耐药机制研究进展

郭雷雷, 徐郁蕊, 张蕾, 董怡文, 林舒婷, 宁兴海, 刘潇璇

郭雷雷, 徐郁蕊, 张蕾, 董怡文, 林舒婷, 宁兴海, 刘潇璇. 三维肿瘤球模型应用于肿瘤耐药机制研究进展[J]. 中国药科大学学报, 2018, 49(5): 521-527. DOI: 10.11665/j.issn.1000-5048.20180502
引用本文: 郭雷雷, 徐郁蕊, 张蕾, 董怡文, 林舒婷, 宁兴海, 刘潇璇. 三维肿瘤球模型应用于肿瘤耐药机制研究进展[J]. 中国药科大学学报, 2018, 49(5): 521-527. DOI: 10.11665/j.issn.1000-5048.20180502
GUO Leilei, XU Yurui, ZHANG Lei, DONG Yiwen, LIN Shuting, NING Xinghai, LIU Xiaoxuan. Advances in the application of three-dimensional tumor spheroids model in the mechanism study of drug resistance[J]. Journal of China Pharmaceutical University, 2018, 49(5): 521-527. DOI: 10.11665/j.issn.1000-5048.20180502
Citation: GUO Leilei, XU Yurui, ZHANG Lei, DONG Yiwen, LIN Shuting, NING Xinghai, LIU Xiaoxuan. Advances in the application of three-dimensional tumor spheroids model in the mechanism study of drug resistance[J]. Journal of China Pharmaceutical University, 2018, 49(5): 521-527. DOI: 10.11665/j.issn.1000-5048.20180502

三维肿瘤球模型应用于肿瘤耐药机制研究进展

基金项目: 国家自然科学基金资助项目(No.51773227,No.81701815,No.21472090);江苏省自然科学基金资助项目(No.BK20170735);中组部“千人计划”青年项目;江苏省“高层次创新创业人才引进计划”资助项目;江苏省六大人才高峰计划资助项目;中国药科大学天然药物活性组分与药效国家重点实验室资助项目(No.SKLNMZZRC201804,No.SKLNMKF201703)

Advances in the application of three-dimensional tumor spheroids model in the mechanism study of drug resistance

  • 摘要: 相比于传统的二维肿瘤细胞培养,三维肿瘤球技术不仅为肿瘤细胞提供与体内相似的生长环境,而且还能最大程度地维持肿瘤细胞的生理功能,因此广泛地应用于肿瘤学研究。特别是三维肿瘤球保留了体内细胞所处微环境的物质及结构基础,更接近于实际的病理生理环境,提高了肿瘤细胞对药物的耐受性,是评价肿瘤治疗手段和肿瘤耐药研究的理想体外模型。本文重点综述了三维肿瘤球形态及微环境诱导产生耐药机制方面的研究,并提出现阶段三维肿瘤球模型存在的问题及今后的发展方向。
    Abstract: In comparison with the traditional two-dimensional tumor cell culture, the three-dimensional tumor spheroid culture can not only provide with an in vivo-like growth environment for tumor cells, but also maintain maximum cell activities. Therefore, the three-dimensional tumor spheroid culture is widely used in oncology research. In particular, the three-dimensional tumor cells retain the material and structural basis of the microenvironment of tumor in vivo, which is closer to the actual physiological environment, allowing it to be an ideal in vitro model for evaluating the tumor treatment response and drug resistance in tumors. This review summarizes the mechanisms of drug resistance in three-dimensional tumor cells, especially those induced by the morphology and microenvironment of three-dimensional tumor spheres, and puts forward the problems existing in the current three-dimensional tumor cells model, as well as the future development direction.
  • [1] Liu YH,Zhong JP,Huo MR.Advances in the tumor microenvironment-responsive smart drug delivery nanosystem[J].J China Pharm Univ(中国药科大学学报),2016,47(2):125-133.
    [2] Palma MD,Biziato D,Petrova TV.Microenvironmental regulation of tumour angiogenesis[J].Nat Rev Cancer,2017,17(8):457-474.
    [3] Dai Y, Xu C, Sun X, et al. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment[J].Chem Soc Rev,2017,46(12):3830-3852.
    [4] Thienpont B,Steinbacher J,Zhao H,et al.Tumor hypoxia causes DNA hypermethylation by reducing TET activity[J].Nature,2016,537(7618):63-68.
    [5] Milosevic MF,Fyles AW,Wong R,et al.Interstitial fluid pressure in cervical carcinoma[J].Cancer,2015,82(12):2418-2426.
    [6] Multhaupt HA,Leitinger B,Gullberg D,et al.Extracellular matrix component signaling in cancer[J].Adv Drug Deliv Rev,2016,97:28-40.
    [7] Ravi M,Ramesh A,Pattabhi A.Contributions of 3D cell cultures for cancer research[J].J Cell Physiol,2017,232(10):2679-2697.
    [8] Nath S, Devi GR. Three-dimensional culture systems in cancer research:focus on tumor spheroid model[J].Pharmacol Ther,2016,163:94-108.
    [9] Weiswald LB,Bellet D,Dangles-Marie V.Spherical cancer models in tumor biology[J].Neoplasia,2015,17(1):1-15.
    [10] Huang SL,Zhao L,Guo QL,et al.Advances of Hedgehog pathway in tumor resistance[J].J China Pharm Univ(中国药科大学学报),2016,47(3):259-266.
    [11] Jiguet JC,Baeza-Kallee N,Denicolaï E,et al.Ex vivo cultures of glioblastoma in three-dimensional hydrogel maintain the original tumor growth behavior and are suitable for preclinical drug and radiation sensitivity screening[J].Exp Cell Res,2014,321(2):99-108.
    [12] Raghavan S,Ward MR,Rowley KR,et al.Formation of stable small cell number three-dimensional ovarian cancer spheroids using hanging drop arrays for preclinical drug sensitivity assays[J].Gynecol Oncol,2015,138(1):181-189.
    [13] Minchinton AI,Tannock IF.Drug penetration in solid tumours[J].Nat Rev Cancer,2006,6(8):583-592.
    [14] Li MY,Lyu HX.Construction and application of three-dimensional tumor spheroid[J].Prog Pharm Sci(药学进展),2017,41(4):285-289.
    [15] Benien P, Swami A. 3D tumor models: history, advances and future perspectives[J].Future Oncol,2014,10(7):1311-1327.
    [16] Fennema E,Rivron N,Rouwkema J,et al.Spheroid culture as a tool for creating 3D complex tissues[J].Trends Biotechnol,2013,31(2):108-115.
    [17] Pavan Grandhi TS,Potta T,Nitiyanandan R,et al.Chemomechanically engineered 3D organotypic platforms of bladder cancer dormancy and reactivation[J].Biomaterials,2017,142:171-185.
    [18] Arai K,Itho M,Mizuno A,et al.Development of spheroid based high-throughput screening of cell-cell adhesion inhibitors to reverse acquired multicellular resistance[J].Cancer Res,2014,74(19 Suppl):697.
    [19] Olive PL,Durand RE.Drug and radiation resistance in spheroids:cell contact and kinetics[J].Cancer Metastasis Rev,1994,13(2):121-138.
    [20] Bates RC,Buret A,Helden DFV,et al.Apoptosis induced by inhibition of intercellular contact[J].J Cell Biol,1994,125(2):403-415.
    [21] Wang Y,Huang Y,Xu X,et al.Expression of small glutamine-rich TPR-containing protein A(SGTA)in non-Hodgkin′s lymphomas promotes tumor proliferation and reverses cell adhesion-mediated drug resistance(CAM-DR)[J].Leuk Res,2014,38(8):955-963.
    [22] Durand RE, Sutherland RM. Effects of intercellular contact on repair of radiation damage[J].Exp Cell Res,1972,71(1):75-78.
    [23] Westhoff MA,Fulda S.Adhesion-mediated apoptosis resistance in cancer[J].Drug Resist Updat,2009,12(4/5):127-36.
    [24] Bai C, Yang M, Fan Z, et al. Associations of chemo- and radio-resistant phenotypes with the gap junction,adhesion and extracellular matrix in a three-dimensional culture model of soft sarcoma[J].J Exp Clin Cancer Res,2015,34:58.
    [25] Croix BS, Flørenes VA, Rak JW, et al. Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents[J].Nat.Med,1996,2(11):1204-1210.
    [26] Folkman J,Moscona A.Role of cell shape in growth control[J].Nature,1978,273(5661):345-349.
    [27] Olive PL,Macphail SH.Radiation-induced DNA unwinding is influenced by cell shape and trypsin[J].Radiat Res,1992,130(2):241-248.
    [28] Raz S,Sheban D,Gonen N,et al.Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest[J].Cell Death Dis,2014,5(2):e1067.
    [29] J Å e,Annadurai N,Frydrych I,et al.Peloruside A-induced cell death in hypoxia is p53 dependent in HCT116 colorectal cancer cells[J].J Nat Prod,2018,81(3):634-640.
    [30] Chang L, Liu X, Wang D, et al. Hypoxia-targeted drug Q6 induces G2-M arrest and apoptosis via poisoning topoisomerase II under hypoxia[J].PLoS One,2015,10(12):e0144506.
    [31] Azad MB,Chen Y,Henson ES,et al.Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3[J].Autophagy,2014,4(2):195-204.
    [32] Li X,Liu X,Xu Y,et al.KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α[J].Int J Oncol,2014,45(4):1507-1514.
    [33] Kim JW, Ho WJ, Wu BM. The role of the 3D environment in hypoxia-induced drug and apoptosis resistance[J].Anticancer Res,2011,31(10):3237-3245.
    [34] Qin Y,Roszik J,Chattopadhyay C,et al.Hypoxia-driven mechanism of vemurafenib resistance in melanoma[J].Mol Cancer Ther,2016,15(10):2442-2454.
    [35] Sonveaux P,Végran F,Schroeder T,et al.Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice[J].J Clin Invest,2008,118(12):3930-3942.
    [36] Spugnini EP, Sonveaux P, Stock C, et al. Proton channels and exchangers in cancer[J].Biochim Biophys Acta,2015,1848(10 Pt B):2715-2726.
    [37] Mehdi D,Wojtkowiak JW,Gillies RJ.pH sensing and regulation in cancer[J].Front Physiol,2013,4(370):370.
    [38] Rauch C.On the relationship between drug′s size,cell membrane mechanical properties and high levels of multi drug resistance:a comparison to published data[J].Eur Biophys J,2009,38(4):537-546.
    [39] Panagiotopoulou V,Richardson G,Jensen OE,et al.On a biophysical and mathematical model of Pgp-mediated multidrug resistance:understanding the “space-time” dimension of MDR[J].Eur Biophys J,2010,39(2):201-211.
    [40] Patel KJ,Trédan O,Tannock IF.Distribution of the anticancer drugs doxorubicin,mitoxantrone and topotecan in tumors and normal tissues[J].Cancer Chemother Pharmacol,2013,72(1):127-138.
    [41] Pan ST,Li ZL,He ZX,et al.Molecular mechanisms for tumour resistance to chemotherapy[J].Clin Exp Pharmacol Physiol,2016,43(8):723-737.
    [42] Luciani F,Spada M,De MA,et al.Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs[J].J Natl Cancer Inst,2004,96(22):1702-1713.
    [43] Pettersson OA,Olsson P,Lindström P,et al.Penetration and binding of L- and D-carboranylalanine in human melanoma spheroids[J].Melanoma Res,1993,3(5):369-376.
    [44] Beaumont KA,Hill DS,Daignault SM,et al.Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells[J].J Invest Dermatol,2016,136(7):1479-1489.
    [45] Haass NK, Beaumont KA, Hill DS, et al. Real-time cell cycle imaging during melanoma growth,invasion,and drug response[J].Pigment Cell Melanoma Res,2015,27(5):764-776.
    [46] Visconti R,Monica RD,Grieco D.Cell cycle checkpoint in cancer:a therapeutically targetable double-edged sword[J].J Exp Clin Cancer Res,2016,35(1):153.
    [47] Santini MT,Rainaldi G,Indovina PL.Apoptosis,cell adhesion and the extracellular matrix in the three-dimensional growth of multicellular tumor spheroids[J].Crit Rev Oncol Hematol,2000,36(2):75-87.
    [48] Berton S, Cusan M, Segatto I, et al. Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells[J].Sci Rep,2017,7(1):595.
    [49] Fu Z, Wang F, Cai J. Gene expression changes in residual advanced cervical cancer after radiotherapy:indicators of poor prognosis and radioresistance[J]?Med Sci Monit,2015,21:1276-1287.
    [50] Sethi T,Rintoul RC,Moore SM,et al.Extracellular matrix proteins protect small cell lung cancer cells against apoptosis:a mechanism for small cell lung cancer growth and drug resistance in vivo[J].Nat Med,1999,5(6):662-668.
    [51] Zanoni M,Piccinini F,Arienti C,et al.3D tumor spheroid models forin vitrotherapeutic screening:a systematic approach to enhance the biological relevance of data obtained[J].Sci Rep,2016,6:19103.
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  • 刊出日期:  2018-10-24

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